In Vivo siRNA Delivery to Immunosuppressive Liver Macrophages by α-Mannosyl-Functionalized Cationic Nanohydrogel Particles.

Macrophages are the front soldiers of the innate immune system and are vital for immune defense, tumor surveillance, and tissue homeostasis. In chronic diseases, including cancer and liver fibrosis, macrophages can be forced into an immunosuppressive and profibrotic M2 phenotype. M2-type macrophages overexpress the mannose receptor CD206.

Overcoming the barrier of CD8T cells: Two types of nano-sized carriers for siRNA transport.

Bioengineering immune cells via gene therapy offers treatment opportunities for currently fatal viral infections. Also cell therapeutics offer most recently a breakthrough technology to combat cancer. These primary human cells, however, are sensitive to toxic influences, which make the utilization of optimized physical transfection techniques necessary.

α-Mannosyl-Functionalized Cationic Nanohydrogel Particles for Targeted Gene Knockdown in Immunosuppressive Macrophages.

Immunosuppressive M2 macrophages govern the immunophathogenic micromilieu in many severe diseases including cancer or fibrosis, thus, their re-polarization through RNA interference is a promising concept to support combinatorial therapies. For targeted siRNA delivery, however, safe and stable carriers are required that manage cell specific transport to M2 macrophages. Here, siRNA-loaded cationic nanogels are reported with α-mannosyl decorated surfaces that target and modify M2 macrophages selectively.

Cationic Nanohydrogel Particles for Therapeutic Oligonucleotide Delivery.

Short pharmaceutical active oligonucleotides such as small interfering RNA (siRNA) or cytidine-phosphate-guanosine (CpG) are considered as powerful therapeutic alternatives, especially to medicate hard-to-treat diseases (e.g., liver fibrosis or cancer).

SiRNA-mediated in vivo gene knockdown by acid-degradable cationic nanohydrogel particles.

Cationic nanohydrogel particles have become an attractive tool for systemic siRNA delivery, but improvement of their in vivo tolerance is desirable, especially to prevent potential long term side effects by tissue and cellular accumulation. Here, we designed novel ketal cross-linked cationic nanohydrogel particles that were assessed for reduced tissue accumulation and robust siRNA delivery in vitro and in vivo. An oligo-amine cross-linker equipped with a ketal moiety in its core was synthesized and applied to nanohydrogel cross-linking of self-assembled reactive ester block copolymers in DMSO.